Chronic renal failure patients who are presensitized to histocompatibility antigens, presumably through exposure by pregnancy, blood transfusions and perhaps bacterial infections, have a documented high failure rate of kidney transplants. Presensitization seems to have more influence on the outcome of transplantation than does pairing of donor and recipients by HLA antigens. The routine method for detection of presensitization is relatively insensitive and recognizes only complement-dependent antibody to HLA. There are data to suggest that other functional antibody classes are raised in response to histocompatibility antigens and that these could prejudice survival of a transplant. Even transplants between donor-recipient combinations that are HLA-identical have a documented failure rate from immunologic causes that implicate the participation of non-HLA systems as major histocompatibility antigens. On the other hand, other classes of antibody of other specificities may have a salutary effect on graft survival. These antibodies may reflect an induced immunologic alteration that modulates a primarily detrimental response to graft antigens and contributes to eventual immunologic adaptation to the graft. We have developed an argument that suggests an intriguing, if complex, interrelationship among diverse antigen systems and their correspondingly diverse antibodies, raised by the alloimmunization of blood transfusions, multiple pregnancies and allografts, and include autoantigens, alloantigens and xenoantigens. The program is directed to improved detection of pre- and posttransplantation antibody responses, including complement-dependent leukocytotoxins of varying thermal amplitude, anti-B cell antibodies, antibodies active in the antibody-dependent cellular cytotoxicity reaction, antibodies recognizing the vascular endothelial-monocyte antigen system, auto-anti-Ii isoagglutinins and heterophile antibodies. The specificities of these antibody classes will be studied using a program of cross adsorptions. The incidence and specificity of antigen presensitization and posttransplant antibody development will be correlated with the outcome of human kidney transplants.